PIM kinase family consists of three homologous serine/threonine kinases, Pim-1, Pim-2, and Pim-3, which belongs to calmodulin-dependent protein kinase-related family (CAMK). Researchers have shown that PIM kinases are widely expressed in hematopoietic tissues (J. Biol. Chem., 280, 14168-14176, 2005; Blood, 105, 4477-4483, 2005) and play important roles in cell survival and proliferation. Since PIM kinases are overexpressed in a variety of malignancies and inflammations (J. Exp. Med., 201, 259-266, 2005; Biochem. Soc. Trans., 32, 315-319, 2004), they are more and more being targeted for treating cancers and immune dysfunctions. PIM-1 (Provirus Integration of Maloney 1) is originally identified in a series of insertional mutagenesis studies of retroviruses, as a frequent proviral integration site in Moloney murine leukemia virus-induced T-cell lymphomas, and PIM-1 is named based on that finding (Cell, 37, 141-150, 1984). It is found later that the genes encoding PIM-2 (Provirus Integration of Maloney 2) have the same defect (J. Clin. Invest., 115, 2679-2688, 2005). Pim-2 has similar effects as and compensatory to Pim-1 (J EMBO, 14, 2536, 1995). PIM-3 is initially named as KID-1 (Kinase Induced by Depolarization 1), but renamed to Pim-3 because of its high sequence similarity to Pim-1 (Nature, 428, 332-337, 2005; Cell, 56, 673-682, 1989). PIM-1, 2, 3 are overly expressed in many hematopoietic malignancies (Proc. Natl. Acad. Sci. U.S.A., 86, 8857-8861, 1989). PIM-1 is found to be overexpressed in the development of prostate cancer (J. Clin. Pathol., 59, 285-288, 2006). PIM-2 expression is elevated in human chronic lymphocytic leukemia and non-Hodgkin's lymphoma leukemia (Leuk. Lymph., 45, 951-955, 2004), the aberrant expression of PIM-3 is believed to have played an important role in the development and proliferation of liver fibroma (Int. J. Cancer, 114, 209-218, 2005) and pancreatic cancer (Cancer Res., 66, 6741-6747, 2006).
PIM-1, PIM-2, and PIM-3 have effects on the survival and proliferation of hematopoietic cells in response to growth factors stimulation. PIM-1, 2, 3 triple knockout mice are viable and fertile while displaying reduced body size and impairment of proliferation of hematopoietic cells in response to growth factors. Knocking out one of 3 kinases does not have obvious effect on mice, indicating some overlapping functions among PIM kinases (Cell, 56, 673-682, 1989). The substrates of PIM kinases include Bcl-2 family members such as pro-apoptotic BAD protein (FEBS Letters, 571, 43-49, 2004), cell cycle regulating p21 (Biochem. Biophys. Acta, 1593, 45-55, 2002), CDC25A, C-TA (J. Biol. Chem., 279, 48319-48328, 2004), protein synthesis related 4EBP1 (Blood, 105, 4477-4483, 2005). These functions of PIM kinases indicate that PIM kinases can prevent apoptosis and promote cell growth and proliferation. Their overexpression in cancer cells promotes the survival and proliferation of the cancer cells. Therefore, inhibiting the PIM kinase activities in cancer cell is a new effective way of treating cancers.
Based on the evidence that PIM kinases are involved in hematological cancers and solid tumors, a number of PIM inhibitors have been developed to treat a variety of cancers. It is shown in a series of cellular assays and in vivo models that PIM inhibitors can significantly inhibit Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic myelogenous leukemia (CML), Non-Hodgkin's Lymphoma (NHL), and Multiple Myeloma (MM) cell proliferation and tumor growth in xenograft model (Clin. Cancer Res. 20(7), 1834-1845, 2014; Blood 123(6), 905-913, 2014; Blood 122(21), 4435, 2013). It has also been demonstrated that PIM inhibitors are useful to treat PIM overexpressed solid tumors such as pancreatic cancers (Cancer Biol. Ther. 7(9), 1352-9, 2008 Cancer Res. 2006; 66(13):6741-7; Cancer Res. 70(24), 10288-10298, 2010), prostate cancers (Prostate, 65(3), 276-86, 2005; Prostate, 73(13), 1462-1469, 2013), liver cancers (J. Surg. Res., 153(1), 17-22, 2009; Int. J. Cancer, 114(2), 209-18, 2005), gastric cancer (J. Cancer Res. Clin. Oncol., 134(4), 481-8, 2008), and bladder cancer (J. Exp. Clin. Cancer Res., 29, 161, 2010).
Moreover, resistance to chemotherapeutics and molecularly targeted drugs is a major obstacle in cancer treatment (Drug Resistance Updat. 12, 114-126. 2009). It has also been reported that PIM kinases are involved in the expression and activity of MDR-1 and BCRP, two of the most important drug efflux transporters. “It is abundantly clear from the preclinical models that PIM inhibition can significantly reverse drug resistant phenotypes.” See Drug Resistance Updates, 14, 203-211, 2011. It has been demonstrated that the use of PIM inhibitors in combination with chemotherapeutics can significantly increase their potencies against drug resistant prostate cancer (Mol. Cancer Ther. 8, 2882-2893, 2009). Therefore, PIM kinase inhibitors are used to reverse the multi drug resistance.
Further, PIM kinases are expressed following T cell activation. Studies show that therapeutic dosing of a PIM-1/3 inhibitor is efficacious in a CD4+ T cell-mediated model of inflammatory bowel disease. Oral administration of AR452530 significantly decreases colon inflammation, gland loss, edema, and mucosal thickness by at least 80%. Therefore, PIM-1/3 kinases have an important role in CD4+ T cell responses and inhibition of this activity may provide a therapeutic benefit in T cell-mediated diseases. See Cellular Immunology, 272, 200-213, 2012.